Transcript PowerPoint Presentation - Slide 1

Metabola Syndromet
2006
Björn Carlsson
Apex Block III, delkurs IV HT 2006
INTER-HEART: Population-attributable risk of
acute MI in the overall population
”Disease” related risk factors
- Diabetes
- Hypertension
- Abdominal obesity
- ApoB/ApoA1
Behaviour related risk factors
Alcohol intake
Exercise
Psychosocial stress
Current smoking
Life style is a Driver of CVD
Physical
inactivity
Life style
intervention
Excessive
food intake
Stress
Smoking
Obesity
Hypertension
Risk factor
modification
Diabetes
Dyslipidaemia
Atherosclerosis
Chronic
heart failure
Atherosclerosis
Arterial & venous
thrombosis/
cardiac & cerebral events
Arrhythmia
Obesity in the US 1985
Obesity in the US 1990
Obesity in the US 1993
Obesity in the US 1998
Obesity in the US 2001
Today 30% of adults in the US are obese and
>65% are overweight
Obesity is a major driver of obesity and diabetes
From Mokdad et al, JAMA 2003
Diabetes/obesity
Pandemic of obesity and type 2 diabetes
mellitus continues
Foreseen effects in the USA
– Life time risk of developing diabetes for
individuals born in 2000
• Men 32.8%
• Women 38.5%
– Life expectancy reduction if diabetes
diagnosed at age <40
• Men: loss of 11.6 life years
• Women: 14.3 life years
Ref. JAMA. 2003;209:1884-90.
Metabolic Syndrome 2005
A cluster of “non-typical” CV risk factors
Increases lifetime risk of developing
type II diabetes and cardiovascular
diasese
Controversial disease etiology
– Insulin resistance
– Visceral obesity
Metabolic Syndrome 2005
IDF Consensus
definition
(a)
ATPIII: the
metabolic
syndrome
(b)
WHO
(c)
EGIR
(d)
Hyper TG waist
(e)
AACC
(f)
International Diabetes
Federation & input from
IAS/NCEP
National
Cholesterol
Education Program
– Adult Treatment
Panel III
1999 World Health
Organization
definition of the
metabolic syndrome
European Group for
the Study of Insulin
Resistance (IR)
The
Hypertriglyceridemic
Waist in Men
American Association of
Clinical
Endocrinologists**
Defined as abdominal
obesity (as measured by
waist circumference
against ethnic and
gender specific cutpoints) plus any two of
the following:
 Hypertriglyceridemia
(> 150 mg/dl; 1.7mmol/l)
 Low HDLc (<40 mg/dl
or <1.03mmol/l for men
and <50 mg/dl or 1.29
mmol/l) for women) or on
treatment for low HDL
 Hypertension (SBP >
130 mmHg DBP > 85
mmHg or on treatment
 Hyperglycemia –
Fasting Plasma Glucose
> 100 mg/dl or 5.6
mmol/l or IGT or preexisting diabetes
mellitus)
Diagnosis is
established when >
3 of these risk
factors are present
 Abdominal
obesity (waist
circumference)
Men >102 cm
(>40 in)
Women >88 cm
(>35 in)
 Hypertriglycerid
emia
> 150 mg/dL
 Low HDLc
Men <40 mg/dL
Women <50 g/dL
 Hypertension
>130/>85 mm Hg
 Hypergylcemia
Fasting Plasma
Glucose >110
mg/dL
Defined as Insulin
Resistance (IR)*
plus any two of the
following:
 Obesity BMI (>30
kg/m2) and/or WHR
(>0.90 in men,
>0.85 in women)
 Hypertriglyceride
mia (>1.7 mmol/l)
and/or low HDL
cholesterol (<0.9
mmol/l in men, <1.0
mmol/l in women)
 Hypertensive .
antihypertensive
treatment and/or
elevated blood
pressure (>140
mmHg systolic or
>90 mmHg
diastolic)
 Microalbuminuria
(urinary albumin
excretion rate
(AER) >30 µg/min
 IR: Fasting
insulin highest 25%
of population
Plus two of the
following:
 Abdominal
obesity (waist
circumference) Men
>94 cm: women
>80 cm
 Hypertriglyceride
mia >2 mmol/l
 And/or low HDLc
<1 mmol/l
 Hypertension
>140/90 mm Hg
 Hyperglycaemia
Fasting plasma
glucose >6.1 mmol/l
 Triglyceride >2.0
mmol/l
 Waist >90 cm
 BMI >25 kg/m2
 Tg >150 mg/dl
 HDLcMen <40 mg/dl
Women <50 mg/dl
 Bp >130/85 mmHg
 2 hours post glucose
challenge BS >140
mg/dl
 Fasting glucose 110126 mg/dl
 Others
 Family history T2DM,
HTN or CVD
 PCO
 Sedentary
 Advancing Age
 Ethnic group at high
risk
Targeting cardiometabolic
risk in patients with
intra-abdominal adiposity
and related comorbidities
Summary
Despite therapeutic advances, cardiovascular disease remains the
leading cause of death worldwide
Current treatments generally target individual risk factors and do not
propose a comprehensive approach to the management of
cardiometabolic disease
An increased risk of developing cardiometabolic disease can be
attributed to abdominal obesity (as measured by waist circumference)
A major cause of cardiometabolic disorders (including dyslipidaemia,
insulin resistance, type 2 diabetes, metabolic syndrome, inflammation
and thrombosis) is thought to be intra-abdominal adiposity (IAA)
Waist circumference provides a simple and practical diagnosis of IAA in
patients at elevated CV risk
theheart.org
500
No. of deaths
(left axis)
400
300
Male
Female
% of all deaths
(right axis)
200
100
0
35
30
25
20
15
10
5
0
Heart
disease and
stroke
Cancer
Accidents
Data for 2002
National Center for Health Statistics 2004
Chronic
lower resp.
disease
Diabetes
% All deaths (male + female)
Number of deaths (thousands)
Despite therapeutic advances,
cardiovascular disease remains the
leading cause of death (USA)
Multiple cardiovascular risk factors
drive adverse clinical outcomes
Increased Cardiometabolic Risk
Dyslipidaemia
Hypertension
Abdominal
obesity
Metabolic Syndrome
Glucose intolerance
Insulin resistance
Substantial residual cardiovascular
risk in statin-treated patients
The MRC/BHF Heart Protection Study
% Patients
30
Placebo
Statin
20
Risk reduction=24%
(p<0.0001)
19.8% of statin-treated
patients had a major
CV event by 5 years
10
0
0
1
2
3
4
Year of follow-up
Heart Protection Study Collaborative Group (2002)
5
6
Unmet clinical needs to address in
the next decade
Major Unmet Clinical Need
Classical Risk Factors
Novel Risk Factors
Metabolic syndrome
HDL-C
 LDL-C
 BP
TNF IL-6
Insulin
Abdominal
Smoking
Obesity
Glu
TG
PAI-1
CARDIOVASCULAR DISEASE
T2DM
Management of the metabolic
syndrome
Appropriate and aggressive therapy is essential for reducing
patient risk of cardiovascular disease
Lifestyle measures should be the first action
Pharmacotherapy should have beneficial effects on
–
Glucose intolerance / diabetes
–
Obesity
–
Hypertension
–
Dyslipidemia
Ideally, treatment should address all of the components of the
syndrome and not the individual components
International Diabetes Federation, 1st International Congress on
“Prediabetes” and Metabolic Syndrome (2005)
Abdominal obesity: required for
diagnosing the metabolic syndrome
IDF criteria of the metabolic syndrome
High waist circumference
Plus any two of
 Triglycerides ( 1.7 mmol/L [150 mg/dL])‡
 HDL cholesterol‡
– Men
< 1.0 mmol/L (40 mg/dL)
– Women < 1.3 mmol/L (50 mg/dL)
 Blood pressure  130 / >85 mm Hg‡
 FPG ( 5.6 mmol/L [100 mg/dL]), or diabetes
‡or
specific treatment for these conditions
International Diabetes Federation (2005)
Abdominal obesity and waist
circumference thresholds
New IDF criteria:
Men
Women
Europid
>94 cm (37.0 in)
>80 cm (31.5 in)
South Asian
>90 cm (35.4 in)
>80 cm (31.5 in)
Chinese
>90 cm (35.4 in)
>80 cm (31.5 in)
Japanese
>85 cm (33.5 in)
>90 cm (35.4 in)
Current NCEP ATP-III criteria
>102 cm (>40 in) in men, >88 cm (>35 in) in women
NCEP 2002; International Diabetes Federation (2005)
High waist circumference is associated
with multiple cardio vascular risk factors
Prevalence of high waist
circumference
associated with (%)
US population age >20 years
30
20
10
0
Low
HDL-Ca
High
TGb
High
FPGc
High
BPd
a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL;
d>130/85 mmHg; eNCEP/ATP III metabolic syndrome
NHANES 1999–2000 cohort; data on file
>2 risk
factorse
Unmet clinical need associated
with abdominal obesity
CV risk factors in a typical patient with abdominal obesity
Patients with
abdominal obesity
(high waist
circumference) often
present with one or
more additional
CV risk factors
Abdominal obesity has reached
epidemic proportions worldwide
USa
Spainb
Italyc
UKd
Francee
Netherlandsf
Germanyg
Men (%)
Women (%)
Total (%)
36.9
30.5
24.0
29.0
–
14.8
20.0
55.1
37.8
37.0
26.0
–
21.1
20.5
46.0
34.7
31.5
27.5
26.3
18.2
20.3
High waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in women
except in Germany (>103 cm [41 in] and >92 cm [36 in], respectively)
aFord
et al 2003; bAlvarez-Leon et al 2003; cOECI 2004; dRuston et al
2004; eObepi 2003; fVisscher & Seidell 2004; gLiese et al 2001
Growing prevalence of abdominal
obesity
US National Health and
Nutrition Examination Survey (NHANES)
NHANES III
NHANES
(1988–1994)
(1999–2000)
Relative
change
Men
29.5%
36.9%
+ 28%
Women
46.7%
55.1%
+ 18%
Abdominal obesity defined as waist circumference: >102 cm (>40 in)
in men or >88 cm (>35 in) in women
Ford et al 2003
Abdominal obesity increases the
risk of developing type 2 diabetes
24
Relative risk
20
16
12
8
4
0
<71
71–75.9
76–81
81.1–86
86.1–91 91.1–96.3
Waist circumference (cm)
Carey et al 1997
>96.3
Metabolic syndrome has a negative
impact on CV health and mortality
No metabolic syndrome
Metabolic syndrome
25
25
*
20
*p<0.001
Mortality rate (%)
Prevalence (%)
20
15
10
*
*
5
*p<0.001
*
15
*
10
5
0
0
CHD
MI
Isomaa et al 2001
Stroke
All-cause Cardiovascular
mortality
mortality
Abdominal obesity: a major underlying
cause of acute myocardial infarction
Cardiometabolic risk factors in the InterHeart Study
60
PAR (%)a
49
Abdominal obesity predicts the
risk of CVD beyond BMI
40
20
20
18
10
0
Abn Lipids
aProportion
Abdom.
Obesity
HTN
Diabetes
of MI in the total population attributable to a specific risk factor
Yusuf et al 2004
Abdominal obesity and increased
risk of cardiovascular events
Adjusted relative risk
The HOPE Study
Waist
circ. (cm):
1.4
Men
Tertile 1
<95
Tertile 2 95–103
Tertile 3 >103
1.29
1
1
1.35
1.27
1.17
1.2
Women
<87
87–98
>98
1.16
1
1.14
1
0.8
CVD death
MI
All-cause deaths
Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-C, total-C
Dagenais et al 2005
Abdominal obesity predicts adverse
outcomes such as sudden death
The Paris Prospective Study
3
4
p for trend
=0.0003
Age-adjusted
relative risk
Age-adjusted
relative risk
4
2
1
0
1
2 3
4
5
Quintile of sagittal
abdominal diameter (SAD)
Quintile
SAD (cm)
BMI (kg/m2)
1
12–19
<23.2
Empana et al 2004
2
20–21
23.2–24.9
3
SAD is a better
predictor of
risk of sudden
death than BMI
2
1
0
3
22–23
25.0–26.6
1
2 3
4
5
Quintile of BMI
4
24
26.7–28.4
5
25–35
28.5–47.7
Abdominal obesity and
increased risk of CHD
Waist circumference was independently associated with
increased age-adjusted risk of CHD, even after adjusting for
BMI and other CV risk factors
3.0
Relative risk
2.5
2.31
p for trend = 0.007
2.44
2.06
2.0
1.5
1.27
1.0
0.5
0.0
<69.8
69.8-<74.2
74.2-<79.2
79.2-<86.3
Quintiles of waist circumference (cm)
Rexrode et al 1998
86.3-<139.7
Why is abdominal obesity harmful?
Abdominal obesity
– is often associated with other CV risk factors
– is an independent CV risk factor
Adipocytes are metabolically active
endocrine organs, not simply inert fat
storage
Wajchenberg 2000
Health threat from abdominal obesity is
largely due to intra-abdominal adiposity
Increased Cardiometabolic Risk
Dyslipidemia
Hypertension
Abdominal
Obesity
Intra-Abdominal
Adiposity
Adapted from Eckel et al 2005
Glucose Intolerance
Insulin Resistance
Intra-abdominal adiposity: a root
cause of cardiometabolic disease
Intra-abdominal adiposity is characterised by accumulation of
fat around and inside abdominal organs
Abdominal obesity
(High waist circumference)
Cardiovascular
risk factors
Intra-abdominal
adiposity
CV
disease
Frayn 2002; Caballero 2003; Misra & Vikram 2003
The evolving view of adipose tissue:
an endocrine organ
Old View: inert storage depot
Fatty acids
Current View: secretory/endocrine organ
Glucose
Fed
Tg
Multiple secretory
products
Tg
Tg
Fasted
Fatty acids
Muscle
Glycerol
Liver
Pancreas
Lyon CJ et al 2003
Vasculature
Intra-abdominal adiposity promotes
insulin resistance and increased CV risk
 Secretion of
 Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
 Intra-abdominal
adiposity
 PAI-1
 suppression of
lipolysis by insulin
 FFA
 Insulin resistance
 Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001;
Skurk & Hauner 2004
 Adiponectin
 IL-6
 TNF
Net result:
 Insulin resistance
 Inflammation
Adverse cardiometabolic effects of
products of adipocytes
↑ Lipoprotein lipase
↑ Agiotensinogen
↑ IL-6
Inflammation
Hypertension
↑ Insulin
↑ TNFα
Adipose
tissue
↑ Adipsin
(Complement D)
↓ Adiponectin
Atherosclerosis
↑ FFA
↑ Resistin
↑ Leptin
↑ Lactate
↑ Plasminogen
activator inhibitor-1
(PAI-1)
Thrombosis
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005
Atherogenic
dyslipidaemia
Type
2 diabetes
Properties of key adipokines
Adiponectin
 in IAA
IL-6
 in IAA
TNF
 in IAA
PAI-1
 in IAA
Anti-atherogenic/antidiabetic:
 foam cells
 vascular remodelling
 insulin sensitivity  hepatic glucose output
Pro-atherogenic/pro-diabetic:
 vascular inflammation  insulin signalling
Pro-atherogenic/pro-diabetic:
 insulin sensitivity in adipocytes (paracrine)
Pro-atherogenic:
 atherothrombotic risk
IAA: intra-abdominal adiposity
Marette 2002
Suggested role of intra-abdominal
adiposity and FFA in insulin resistance
Intra
abdominal
adiposity
 Hepatic
insulin
resistance
Portal
circulation
 Hepatic
glucose
output
 FFA
Lipolysis
 TG-rich
VLDL-C
CETP,
lipolysis
Systemic
circulation
FFA: free fatty acids
CETP: cholesteryl ester
transfer protein
Lam et al 2003; Carr et al 2004; Eckel et al 2005
 Small,
dense
LDL-C
Low
HDL-C
 Glucose utilisation
 Insulin resistance
Intra abdominal adiposity impairs
pancreatic b-cell function
 FFA
Splanchnic & systemic
circulation
Intra abdominal
adiposity
Short-term
stimulation
of insulin
secretion
FFA: Free fatty acids
Haber et al 2003; Zraika et al 2002
Long-term damage
to b-cells
Decreased insulin
secretion
Systemic inflammation and adverse
cardiovascular outcomes
Physicians' Health Study: 9-year follow-up
Relative risk of MI
5
4.4
4
2.8
3
1.3
2
2.5
3.4
2.8
1.1
1
1.0
1.2
0
Low
Medium
High
Cholesterol/HDL cholesterol ratio
Ridker et al 1998
Low
High
Medium
Intra-abdominal adiposity and
dyslipidaemia
Triglycerides
HDL-cholesterol
310
60
186
mg/dL
mg/dL
248
124
45
62
30
0
Lean
Low High
Visceral fat
(obese subjects)
Pouliot et al 1992
Lean
Low High
Visceral fat
(obese subjects)
Intra-abdominal adiposity and
glucose metabolism
Glucose
1
9
1
Area
1
1,2
1
1
1,2 1,2
1,2
1,2
1
1
1
pmol/L
mmol/L
12
1,2
1200
800
Area
1
15
6
Insulin
1,2
1,2
1,2
400
3
1,2
1,2
0
0
0
60
120
Time (min)
Non-obese
180
Obese low IAA
0
60
120
Time (min)
Obese high IAA
IAA: intra-abdominal adiposity
Significantly different from 1non-obese, 2obese with low intra-abdominal adiposity
levels
Pouliot et al 1992
180
Pathophysiology of the metabolic syndrome
leading to atherosclerotic CV disease
Genetic variation
Environmental factors
Abdominal obesity
Adipokines
Adipocyte
Cytokines
Inflammatory markers
Insulin resistance
 Tg
Metabolic syndrome
 HDL
 BP
Atherosclerosis
Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005
Cardiovascular events
Monocyte/
macrophage
Summary
Despite therapeutic advances, cardiovascular disease remains the
leading cause of death worldwide
Current treatments generally target individual risk factors and do not
propose a comprehensive approach to the management of
cardiometabolic disease
An increased risk of developing cardiometabolic disease can be
attributed to abdominal obesity (as measured by waist circumference)
A major cause of cardiometabolic disorders (including dyslipidaemia,
insulin resistance, type 2 diabetes, metabolic syndrome, inflammation
and thrombosis) is thought to be intra-abdominal adiposity (IAA)
Waist circumference provides a simple and practical diagnosis of IAA in
patients at elevated CV risk
A Broad Approach to Prevention and Treament of
Cardiovascular Disease
Physical
inactivity
Life style
intervention
Excessive
food intake
Stress
Smoking
Obesity
Risk factor
modification
Disease
intervention/
secondary
prevention
Hypertension
Diabetes
Dyslipidaemia
Atherosclerosis
Chronic
heart failure
Atherosclerosis
Arterial & venous
thrombosis/
cardiac & cerebral events
Arrhythmia
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